NAD+ modulates mitochondrial vulnerability and prevents retinitis pigmentosa

Retinitis pigmentosa (RP) is the most common inherited blinding retinal degenerative disease characterized by the progressive loss of photoreceptors and retinal pigment epithelium (RPE) that eventually causes retinal degeneration. However, the mechanisms that initiate RP and drive retinal vulnerability remain incompletely understood, and new strategies for its prevention and therapy are urgently needed. Mitochondrial dysfunction is the initiator of a variety of neurodegeneration, whether mitochondrial dysfunction is an important pathogenic factor of RP is still unknown. Our single-cell RNA sequencing, transmission electron microscopy, and enzyme-linked immunosorbent assay revealed that both photoreceptor cells and RPE cells of RP rats have abnormal mitochondria, accompanied by decreased levels of nicotinamide adenine dinucleotide (NAD+) metabolism which rendered the lack of NAD+ vulnerable to disease-related insults. Moreover, similar experimental results were observed in an in vitro RP model established by human primary RPE cells. Furthermore, electroretinography combined with hematoxylin-eosin, immunofluorescence analysis, and fundus photograph investigations revealed that oral administration of the NAD+ precursor nicotinamide (NMN) protected RP rats against retinal degeneration. Mechanistically, single-cell RNA sequencing, siRNA targeting, and AAV virus applications demonstrated the therapeutic effect of NMN on RP through the glyceraldehyde-phosphate dehydrogenase-mitochondria pathway. Collectively, these findings indicate that mitochondrial abnormalities may be the drivers of RP and NMN has a therapeutic effect on RP.